Summary Breast cancer is the second most common and the major cause of cancer-related death of women in the USA. The last decade has witnessed major advancement of therapeutic drugs and tools, while noninvasive diagnostic imaging tools to measure interventions received much less attention. Currently, the mainstay of noninvasive imaging in breast cancer relies primarily on anatomic imaging. Metabolic imaging using FDG PET is a successful diagnostic tool in several types of cancer, but not in the setting of breast cancer. The last decade has also witnessed the revival of interest in the role of mitochondria in tumor invasiveness, and as regulators of cytotoxicity of first-line chemotherapy agents. Yet, current tools for noninvasive investigations and diagnostics of the mitochondrial function in cancer patients are limited to SPECT imaging agents. Our recent preclinical studies provided compelling evidence for the capacity of the PET imaging voltage sensor 18F- fluorobenzyltriphenylphosphonium (FBnTP), developed by the PI laboratory, to potentially improve management of breast cancer. This includes: (1) improved early detection of early-stage, small, vascularized breast lesion with better functional and spatial resolution compared to FDG PET and SPECT imaging; (2) Accurate 3D mapping of tumor proliferation, an important prognostic factor in the clinical setting; and (3) very early molecular-level detection of treatment response, directly at the core mechanism of cytotoxicity of first-line chemotherapy agents. The technology supporting these utilities is based on our studies which demonstrate that cellular uptake of FBnTP is directly proportional to the mitochondrial membrane potential (??m) of a cell. ??m is the most comprehensive physiological endpoint of the organelle bioenergetics. ??m is a unique target that enables attaining the above goals. ??m is significantly greater in certain types of malignant cells, including those of breast origin, compared to normal cells, resulting in a preferential accumulation of FBnTP in tumor mass, compared to healthy parenchyma. ??m increases in highly proliferating breast cancer cells, whereas collapse of ??m coincides with the initiation of the irreversible phase of the apoptotic cell death as induced by many first-line chemotherapy agents in the breast cancer setting. The goal of this STTR Phase 1 study is to establish proof of concept in patient samples under the approved IRB that FBnTP is an effective imaging technology to detect breast lesions in women; a prerequisite for future feasibility studies of FBnTP as a surrogate marker of breast tumor invasiveness and response to therapeutic interventions. To improve commercial competitiveness, FBnTP imaging will be carried out using breast- dedicated positron emission mammogram (PEM), a less costly technology, compared to PET, CT and MRI and of better spatial resolution than PET.